Syntheses and biological studies of novel spiropiperazinyl oxazolidinone antibacterial agents using a spirocyclic diene derived acylnitroso Diels-Alder reaction.

Several novel oxazolidinone antibiotics with a spiropiperazinyl substituent at the 4'-position of the phenyl ring were synthesized through nitroso Diels-Alder chemistry and the in vitro antibacterial activities were evaluated against various Gram-positive bacteria (Bacillus subtilis, Staphylococcus aureus, Enterococcus faecalis), Gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa) and mycobacteria (Mycobacterium vaccae, Mycobacterium tuberculosis). Analogs (8a and 12) were active against selected drug resistant microbes, like methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) and had no mammalian toxicity in a Hep-2 cellular assay (CC(50) >100 µM).

Structure-activity relationship of new anti-tuberculosis agents derived from oxazoline and oxazole benzyl esters.

During the syntheses and studies of natural iron chelators (mycobactins), we serendipitously discovered that a simple, small molecule, oxazoline-containing intermediate 3 displayed surprising anti-tuberculosis activity (MIC of 7.7 microM, average). Herein we report elaboration of SAR around this hit as well as the syntheses and evaluation of a hundred oxazoline- and oxazole-containing compounds derived from an efficient three step process: 1) formation of beta-hydroxy amides with serine or threonine; 2) cyclization to afford oxazolines; and 3) dehydration to give the corresponding oxazoles. A number of compounds prepared by this method were shown to possess impressive activity against Mycobacterium tuberculosis, extremely low toxicity and therefore high therapeutic indexes, as well as activity against even the more recalcitrant non-replicating form of M. tuberculosis. The uniqueness of their structures and their simplicity should allow them to be further optimized to meet ADME (absorption, distribution, metabolism, excretion) requirements. The syntheses of eight of the most potent in vitro compounds were scaled up and the compounds were tested in an in vivo mouse infection model to evaluate their efficacy before engaging upon more elaborate compound design and optimization.

Antimicrobial, antiproliferative, cytotoxic, and tau inhibitory activity of rubellins and caeruleoramularin produced by the phytopathogenic fungus Ramularia collo-cygni.

Photodynamically active anthraquinone derivatives produced by the phytopathogenic fungus Ramularia collo-cygni are known to cause a barley leaf-spot disease, but data about light-dependent and independent bioactivity have been sparse to date. We therefore conducted for the first time a broad bioactivity profiling of rubellins B, C, D, and E and caeruleoramularin. Antibacterial but not antiviral activity is reported with light-dependent increase. Furthermore, when tested without illumination, compounds exerted antiproliferative and cytotoxic activity in a series of human tumor cell lines. Inhibition of tau protein assembly was observed as well.

Benzothiazinones kill Mycobacterium tuberculosis by blocking arabinan synthesis.

New drugs are required to counter the tuberculosis (TB) pandemic. Here, we describe the synthesis and characterization of 1,3-benzothiazin-4-ones (BTZs), a new class of antimycobacterial agents that kill Mycobacterium tuberculosis in vitro, ex vivo, and in mouse models of TB. Using genetics and biochemistry, we identified the enzyme decaprenylphosphoryl-beta-d-ribose 2'-epimerase as a major BTZ target. Inhibition of this enzymatic activity abolishes the formation of decaprenylphosphoryl arabinose, a key precursor that is required for the synthesis of the cell-wall arabinans, thus provoking cell lysis and bacterial death. The most advanced compound, BTZ043, is a candidate for inclusion in combination therapies for both drug-sensitive and extensively drug-resistant TB.

Synthesis and studies of catechol-containing mycobactin S and T analogs.

The syntheses of catechol-containing mycobactin S and T analogs are described. These analogs incorporate a catechol-glycine moiety in place of the phenol-oxazoline of the naturally occurring mycobactins S and T. Studies indicated that the new siderophore analogs bind iron, and promote the growth of a number of microbes, especially strains of mycobacteria, as expected.

Alzheimer-like plaque formation by human macrophages is reduced by fibrillation inhibitors and lovastatin.

The cerebral deposition of Abeta-peptide as amyloid fibrils and plaques represents a hallmark characteristic of Alzheimer's disease (AD). AD plaques are defined by their green birefringence after Congo red staining, their spherulite-like superstructure and their association with specific secondary components. Here we show that primary human macrophages promote the formation of amyloid plaques that correspond in all aforementioned characteristics to typical amyloid plaques from diseased tissues: they consist of aggregated Abeta-peptide, they reveal the typical ''Maltese cross" structure and they are associated with the secondary components glycosaminoglycanes, apolipoprotein E (apoE) and the raft lipids cholesterol and sphingomyelin. Plaque formation can be impaired in this cell system by addition of small molecules, such as Congo red, melantonine and lovastatin, suggesting potential applications for the study of cellular amyloid formation and for the identification or validation of drug candidates.